Acceptable Benefit-Risk Profile of Tolvaptan in Number Needed to Harm Analysis

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic kidney disease. ADPKD is associated with a risk for progression to loss of kidney function and kidney failure. Tolvaptan has been approved to slow decline in kidney function in adults with rapidly progressing ADPKD.

The FDA Risk Evaluation and Mitigation Strategy program closely monitors the potential risk of liver injury in patients treated with tolvaptan. Sasikiran Nunna, PhD, Otsuka Pharmaceutical Development & Commercialization, Inc, and colleagues conducted a study to examine the safety profile of tolvaptan related to liver function using the number needed to harm (NNH) approach. Results were reported during a poster session at the American Society of Nephrology Kidney Week 2022 in a poster titled Number Needed to Harm (NNH) Analysis of Tolvaptan in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD).

The analysis utilized individual patient-level data from the TEMPO 3:4 trial to assess abnormalities in liver function, and serious alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation adverse events over 12 and 36 months of treatment. Abnormalities in liver function were defined as ALT >3 times and >5 times of the normal  range. The reciprocal of the difference in the proportion of patients experiencing a given outcome between tolvaptan and placebo was used to calculate NNH.

The cohort included 961 patients in the tolvaptan arm and 483 in the placebo arm. The NNHs for ALT >3 times the upper level of normal were 56.19 (95% CI, 33.60-171.33) over 12 months and 39.81 (95%cI, 25.59-89.57) over 24 months. For every 100 patients treated with tolvaptan rather than placebo, only 1.78 and 2.51 additional patients would  have ALT >3 times the upper level of normal over 12 and 24 months, respectively.

There were no statistically significant differences between the two study arms in the proportion of patients with ALT >5 times the upper level of normal or serious ALT or AST elevation in either time period. The results suggest that for every 100 patients treated with tolvaptan rather than placebo, fewer than one additional patient would experience ALT >5 times the upper level of normal or serious ALT or AST elevation over 12 or 24 months.

“The large NNH values help further characterize the safety profile of tolvaptan by demonstrating an acceptable benefit -risk profile,” the researchers said.

Source: Nunna S, Betts Kam Kumar RK, Nie X, Fernandes A. Number needed to harm (NNH) analysis of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD). TH-PO411. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2022; November 3, 2022; Orlando, Florida. Support was provided by Otsuka Pharmaceutical Development & Commercialization, Inc.